One established method of cancer treatment comprises irradiation by high-energy electromagnetic waves, typically X-rays. Solid tumors contain significant numbers of cells which are distal from the vasculature leading to oxygen deficiency or hypoxia. Hypoxia protects cells from radiotherapy. There is, therefore, a need for compounds which render the hypoxic cells more sensitive to killing by X-rays or the like. These compounds are referred to herein as "radiosensitizers."
A variety of transition metal complexes have been shown to possess radiosensitizer activity. These include complexes of Ag, Cu, Zn, Hg, Pt, Co, Fe and Rh. For a current review, see Kirsten Skow, Radiation Research, 112:217-242 (1987). Copper (II) complexes have been reported possessing radiosensitizer activity and radioprotectant activity. For example, a Cu(II) complex of histamine is reported to possess radiosensitizer activity (see Tonelli, D. et al in 6th Conference on Chemical Modifiers of Cancer Treatment, 1988, p. 2-26), whereas bis(3,5-diisopropylsalicylato)Cu(II) is reported to possess radioprotectant activity (see Sorenson, J. R. J., J. Med. Chem., 27:1747-1749 (1984). Consequently, the presence of a Cu(II) moiety in a complex does not constitute sufficient grounds for predicting that a given complex will possess radiosensitizer activity.
The present invention is based on the finding that certain coordination compounds of copper, namely Cu(II) coordination compounds, render hypoxic cells more sensitive to irradiation.